Alzheimer's Disease is a chronic illness that is age-related in nature. It causes neurological degeneration due to genetic and environmental factors predisposing those afflicted. The disease is characterized by progressive memory loss, cognitive deterioration and behavioral disorders is the most common cause of dementia among elderly people (Goedert, M. et al. (2006) “A Century Of Alzheimer's Disease,” Science. 314(5800):777-781; Pallas, M. et al. (2006) “Molecular And Biochemical Features In Alzheimer's Disease,” Curr Pharm Des. 12(33):4389-4408; Roberson, E. D. et al. (2006) “100 Years And Counting: Prospects For Defeating Alzheimer's Disease,” Science. 314(5800):781-784; Samanta, M. K. et al. (2006) “Alzheimer Disease And Its Management: A Review.” Amer. J. Ther. 13(6):516-526). Alzheimer's Disease is diagnosed in postmortem analysis by the presence of neurofibrillary tangles, senile plaques, and neuronal loss (Selkoe D. J. (1994) “Alzheimer's Disease: A Central Role For Amyloid,” J. Neuropathol. Exp. Neurol. 53:438-447).
The best understood cause for the onset of Alzheimer's Disease is that the disease results from a misfolding and accumulation of two neuronal proteins: the amyloid beta (“Aβ”) protein which is a proteolytic byproduct of the transmembrane protein amyloid precursor protein (APP) and microtubule-associated proteins known as “tau” proteins (Blurton-Jones, M. et al. (2006) “Pathways By Which Abeta Facilitates Tau Pathology,” Curr. Alzheimer Res. 3(5):437-448; Golde, T. E. et al. (2006) “Filling The Gaps In The Aβ Cascade Hypothesis Of Alzheimer's Disease,” Curr. Alzheimer Res. 3(5):421-430; Leissring M A. (2006) “Proteolytic Degradation Of The Amyloid Beta-Protein: The Forgotten Side Of Alzheimer's Disease,” Curr. Alzheimer Res. 3(5):431-435; Ohyagi, Y. et al. (2006) “Intracellular Amyloid Beta-Protein And Its Associated Molecules In The Pathogenesis Of Alzheimer's Disease,” Mini Rev. Med. Chem. 6(10):1075-1080; Urbanc, B. et al. (2006) “Computer Simulations Of Alzheimer's Amyloid Beta-Protein Folding And Assembly,” Curr. Alzheimer Res. 3(5):493-504). Multiple isoforms of Aβ have been identified, ranging from 39-43 amino acid residues in length; the most common isoforms are Aβ40 and Aβ42. The loss of the body's ability to inhibit the mutation of the Aβ peptide occurs in a cascading effect.
The causes of Alzheimer's disease are not purely genetic predisposition. It has also been shown that people who have experienced multiple head injuries or have received high amounts of dietary cholesterol for extended periods are more susceptible to the disease (Canevari, L. et al. (Epub 2006 Dec. 27) “Alzheimer's Disease And Cholesterol: The Fat Connection,” Neurochem Res. 32(4-5):739-750). Factors that may be responsible for a decreased susceptibility to the disease include uptake of estrogens, statins, and non-steroidal anti-inflammatory drugs (Cole G. M. et al. (2004) “NSAID And Antioxidant Prevention Of Alzheimer's Disease: Lessons From In Vitro And Animal Models,” Ann. N.Y. Acad. Sci. 1035:68-84).
The site believed to be responsible for the initial onset of the misfolding proteins is the Aβ(1-42) peptide. A specific mutation or other defect is believed to cause the excessive polymerization of tau proteins from the neural fibrillary tangles. In essence the misfolding of these proteins has a toxic effect on enzymes responsible for correcting the mutating cells. The Aβ(25-35) site has been identified as the toxic fragment of βA(1-42) which causes this neuronal insult to PC12 cells (Park, S. Y. et al. (2002) “Discovery Of Natural Products From Curcuma longa That Protect Cells From Beta-Amyloid Insult. A Drug Discovery Effort Against Alzheimer's Disease,” J. Nat. Prod. 65(9):1227-1231). Once the process has begun, the increased production of Aβ might not be necessary for the toxic effects to increase. Once initiated the polymerized tau proteins will continue to tangle and grow, degenerating neural function as they polymerize. This causes an increased accumulation of excessively tangled fibrils to the point where enzymes can no longer breakdown defective cells and neural pathways begin to degenerate at an increasing rate (Cole G. M. et al. (2004) “NSAID And Antioxidant Prevention Of Alzheimer's Disease: Lessons From In Vitro And Animal Models,” Ann. N.Y. Acad. Sci. 1035:68-84). Treatments for Alzheimer's Disease currently involve the use of non-steroidal anti-inflammatory agents to slow the cascading effect of the disease's progression. To date, no fully successful therapy for Alzheimer's Disease has been developed.
Curcumin is a yellow pigment extracted from the rhizome of the plant Curcuma longa. The compound has been found to have a number of pharmacological activities, and represents a hopeful approach for delaying or preventing the progression of Alzheimer's Disease (Cole G. M. et al. (2004) “NSAID And Antioxidant Prevention Of Alzheimer's Disease: Lessons From In Vitro And Animal Models,” Ann. N.Y. Acad. Sci. 1035:68-84; Bala, K. et al. (2006) “Neuroprotective And Anti-Ageing Effects Of Curcumin In Aged Rat Brain Regions,” Biogerontology 7:81-89). In vitro studies have shown that curcumin attenuates inflammatory response of brain microglial cells (Jung K. K. et al. (2006) “Inhibitory Effect Of Curcumin On Nitric Oxide Production From Lipopolysaccharide-Activated Primary Microglia,” Life Sci. 79:2022-2031; Kim H. Y. et al. (2003) “Curcumin Suppresses Janus Kinase-STAT Inflammatory Signaling Through Activation Of Src Homology 2 Domain-Containing Tyrosine Phosphatase 2 In Brain Microglia,” J. Immunol. 171:6072-6079). Curcumin has also been reported to inhibit the formation of Aβ oligomers and fibrils in vitro (Ono, K. et al. (2004) “Curcumin Has Potent Anti-Amyloidogenic Effects For Alzheimer's Beta-Amyloid Fibrils in vitro,” J. Neurosci. Res. 75, 742-750; Yang, F. et al. (2005) “Curcumin Inhibits Formation Of Amyloid Beta Oligomers And Fibrils, Binds Plaques, And Reduces Amyloid in vivo,” J. Biol. Chem. 280:5892-5901), to prevent neuronal damage (Shukla P. K. et al. (2003) “Protective Effect Of Curcumin Against Lead Neurotoxicity In Rat,” Hum. Exp. Toxicol. 22:653-658), and reduce oxidative damage (Lim, G. P. et al. (2001) “The Curry Spice Curcumin Reduces Oxidative Damage And Amyloid Pathology In An Alzheimer Transgenic Mouse,”. J. Neurosci. 21:8370-8377) and amyloid accumulation (Yang, F. et al. (2005) “Curcumin Inhibits Formation Of Amyloid Beta Oligomers And Fibrils, Binds Plaques, And Reduces Amyloid in vivo,” J. Biol. Chem. 280:5892-5901).
Curcumin has also been found to have anticancer activity, anti-inflammatory activity and immunomodulatory activity (McDonald, R et al. (2001) “Synthesis And Anticancer Activity Of Nordihydroguaiaretic Acid (NDGA) And Analogues,” Anti-Cancer Drug Design 16(6):261-270; Parveen, I., et al. (2000) “Labeled Compounds of Interest as Antitumor Agents,” Chem. Abstract. 133:281645; Martono, S. (1996) “Inhibitory Effects of Curcumin and its Analogs on In Vitro Rat Liver Glutathione S-Transferases Activity,” Chem. Abstract. 128:110377; McDonald et al. (2001) “Synthesis and Anticancer Activity of nordihydrogualaretic Acid and Analogues, Chem. Abstract. 138:362138 (2001); Choshi et al. (1992) “Synthesis of Dibenzoylmethane Derivatives and Inhibition of Mutagenicity in Salmonella typhimurium,” Chem. Abstract. 117:48036; Artiser, J. L. et al. (1998) “Curcumin Is an In Vivo Inhibitor of Angiogenesis,” Molec. Med. 4:376-383; Ishida, J. et al. (2000) “Antitumor-Promoting Effects Of Cyclic Diarylheptanoids On Epstein-Barr Virus Activation And Two-Stage Mouse Skin Carcinogenesis,” Canc. Lett. 159:135-140; Ruby, A. J., et al. (1995) “Anti-Tumour And Antioxidant Activity Of Natural Curcuminoids,” Canc. Lett. 94:79-83; Sugiyama, Y. et al. (1996) “Involvement of the β-Diketone Moiety in the Antioxidantive Mechanism of Tetrahydrocurcumin,” Biochem. Pharmacol. 52:519-525 (1996); Syu, Wan-Jr, et al. (1998) “Cytotoxicity of Curcuminoids and Some Novel Compounds from Curcuma zedoaria,” J. Nat. Prod. 61:1531-1534; Gautam, S. C. et al. (2007) “Immunomodulation By Curcumin,” Adv. Exp. Med. Biol. 595:321-341).
Pharmacological uses of curcumin are reviewed by Garcia-Alloza, M. et al. (e-pub April 2007) “Curcumin Labels Amyloid Pathology In Vivo, Disrupts Existing Plaques, And Partially Restores Distorted Neurites In An Alzheimer Mouse Model,” J. Neurochem. 10.1111/j.1471-4159.2007.04613.x; Lim, G. P. et al. (2001) “The Curry Spice Curcumin Reduces Oxidative Damage And Amyloid Pathology In An Alzheimer Transgenic Mouse,”. J. Neurosci. 21:8370-8377; Ono, K. (2006) “The Development of Preventives and Therapeutics for Alzheimer's Disease that Inhibit the Formation of β-Amyloid Fibrils (fAβ), as Well as Destabilize Preformed fAβ,” Curr. Pharma. Des. 12:4357-4375; Ono, K. et al. (2004) “Curcumin Has Potent Anti-Amyloidogenic Effects For Alzheimer's Beta-Amyloid Fibrils in vitro,” J. Neurosci. Res. 75, 742-750; Ramassamy, C. (2006) “Emerging Role Of Polyphenolic Compounds In The Treatment Of Neurodegenerative Diseases. A Review Of Their Intracellular Targets,” Eur. J. Pharmacol. 545(1):51-64; Ringman, J. M. et al. (2005) “A Potential Role Of The Curry Spice Curcumin In Alzheimer's Disease,” Curr. Alzheimer Res. 2(2): 131-136; and Yang, F. et al. (2005) “Curcumin Inhibits Formation Of Amyloid Beta Oligomers And Fibrils, Binds Plaques, And Reduces Amyloid in vivo,” J. Biol. Chem. 280:5892-5901.
Clinical trials with curcumin have shown that the compound is not only safe but may be a chemoprotective (Cheng A. L. et al. (2001) “Phase I Clinical Trial Of Curcumin, A Chemopreventive Agent, In Patients With High-Risk Or Pre-Malignant Lesions,” Anticancer Res. 21: 2895-2900) and anti-inflammatory (Holt P. R. et al. (2005) “Curcumin Therapy In Inflammatory Bowel Disease: A Pilot Study,” Dig. Dis. Sci. 50:2191-2193) drug.
The isolation of natural curcumin from the Curcuma longa rhizome has proven to be difficult and costly (U.S. Pat. No. 5,679,864 (Krackov et al.); U.S. Pat. No. 6,790,979 (Lee et al.); Pedersen et al. (1985) “Synthesis of Naturally Occurring Curcuminoids and Related Compounds,” Chem. Abstract. 103:178092 (1985); Nurfina, A. N. et al. (1997) “Synthesis Of Some Symmetrical Curcumin Derivatives And Their Anti-Inflammatory Activity, Eur. J. Med. Chem. 32:321-328). Krakov et al. disclose the synthesis of curcumin by reacting the enol form of a 2,4-diketone with a monocarbocyclic aldehyde in the presence of an organic amine catalyst. The reactants are dissolved in a highly polar, aprotic organic solvent. The curcumin-related product is recovered in crystalline form by precipitation from the reaction mass and solvent recrystallization. Other approaches to curcumin synthesis include aldol condensation of vanillin (3-methoxy-4-hydroxybenzaldehyde) and 2,4-pentanedione. However, the yields of product from such synthesis are reported to be very low, in large part because of the difficult and complicated procedures required for isolation and purification of the product. Methods for synthesizing curcumin and its analogues are disclosed in: WO06089894; and in Arieta, A. F. (1994) “Direct Synthesis of Demethoxycurcumin,” C. R. Acad. Sci. Paris, Ser II, 479-482; Pedersen et al. (1985) “Synthesis of Naturally Occurring Curcuminoids and Related Compounds,” Ann. Chem. 15:57-69; Arrieta, A. F. et al. (1991) “Synthesis and H-NMR-Spectroscopic Investigatons of New Curcumin Analogs,” J. Prakt. Chem. 334:656-700; and Roughly et al. (1973) “Experiments in the Biosynthesis of Curcumin,” J. Chem. Soc. Perkins Trans I, I, 23:79-88. Yields or process operability are reported to be poor (U.S. Pat. No. 5,679,864 (Krackov et al.)).
Despite all prior advances, available methods for synthesizing curcumin and its analogues remain labor intensive, time consuming and environmentally unfavorable especially for low purity products. Thus, a need remains for improved methods of synthesizing such compounds. The present invention is directed to this and related needs